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Evaluation of a Radiolabeled Macrocyclic Peptide as Potential PET Imaging Probe for PD−L1
Author(s) -
Jouini Nedra,
Cardinale Jens,
Mindt Thomas L.
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202200091
Subject(s) - internalization , peptide , in vivo , in vitro , chemistry , ligand (biochemistry) , peptide synthesis , cancer research , pd l1 , molecular imaging , cell , combinatorial chemistry , cancer , biochemistry , receptor , immunotherapy , medicine , biology , microbiology and biotechnology
The interaction between the immune checkpoint PD‐1 and PD−L1 promotes T‐cell deactivation and cancer proliferation. Therefore, immune checkpoint inhibition therapy, which relies on prior assessment of the target, has been widely used for many cancers. As a non‐invasive molecular imaging tool, radiotracers bring novel information on the in vivo expression of biomarkers (e. g., PD−L1), enabling a personalized treatment of patients. Our work aimed at the development of a PD−L1‐specific, peptide‐based PET radiotracer. We synthesized and evaluated a radiolabeled macrocyclic peptide adapted from a patent by Bristol Myers Squibb. Synthesis of [ 68 Ga]Ga‐NJMP1 yielded a product with a radiochemical purity>95 % that was evaluated in vitro . However, experiments on CHO−K1 hPD−L1 cells showed very low cell binding and internalization rates of [ 68 Ga]Ga‐NJMP1 in comparison to a control radiopeptide (WL12). Non‐radioactive cellular assays using time‐resolved fluorescence energy transfer confirmed the low affinity of the reported parent peptide and the DOTA‐derivatives towards PD−L1. The results of our studies indicate that the macrocyclic peptide scaffold reported in the patent literature is not suitable for radiotracer development due to insufficient affinity towards PD−L1 and that C‐terminal modifications of the macrocyclic peptide interfere with important ligand/receptor interactions.